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INTRODUCTION: Ultra-rare mendelian osteolytic disorders caused by different length in-frame activating duplications within exon 1 of TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK) comprise familial expansile osteolysis (FEO), expansile skeletal hyperphosphatasia (ESH), early-onset familial Paget's disease of bone (PDB2), juvenile Paget's disease 2 (JPD2), and panostotic expansile bone disease (PEBD). FEO typically presents with childhood-onset deafness followed by resorption of permanent dentition, and then appendicular bone pain, fractures, and deformities from progressive focal expansile osteolytic lesions emerging from a background of generalized high bone turnover. An 18-bp duplication in TNFRSF11A has been reported in all kindreds with FEO, whereas a 12-bp duplication was found in the young man with PEBD complicated by a massive jaw tumor. We report the clinical course and successful treatment with bisphosphonates of a girl with the 12-bp duplication yet a skeletal phenotype seemingly milder than PEBD. CASE PRESENTATION AND DISCUSSION: This 10-year-old girl presented for dental and orthodontic treatment and was found to have progressive external tooth root resorption. Speech delay was identified at age 18 months, and audiological evaluation showed both conductive and sensorineural hearing loss subsequently treated with a cochlear implant at age 3 years. Biochemical studies indicated increased bone turnover with elevated urinary N-telopeptide levels and serum alkaline phosphatase in the upper normal range. Low lumbar spine bone mineral density (BMD) was revealed by dual-energy X-ray absorptiometry, but whole-body Technetium-99 m bone scintigraphy was normal. Genetic testing identified the identical de novo 12-bp duplication within exon 1 of TNFRSF11A harbored by the young man with PEBD and massive jaw tumor. Bisphosphonate treatment, initiated with one dose of intravenous zoledronic acid that caused prolonged hypocalcemia, then comprised weekly oral alendronate that decreased bone turnover markers and normalized her BMD. CONCLUSION: Constitutive activation of RANK signaling should be considered a possible cause in any young person with rapid bone turnover, particularly in the context of early-onset deafness and/or root resorption of permanent teeth. Early diagnosis and anti-resorptive treatment, given judiciously to avoid sudden and prolonged hypocalcemia, may prevent further skeletal disease.
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Enfermedades Óseas Metabólicas , Sordera , Hipocalcemia , Osteítis Deformante , Resorción Radicular , Femenino , Humanos , Enfermedades Óseas Metabólicas/genética , Difosfonatos , FN-kappa B , Osteítis Deformante/diagnóstico por imagen , Osteítis Deformante/tratamiento farmacológico , Osteítis Deformante/genética , Receptor Activador del Factor Nuclear kappa-B/genética , NiñoRESUMEN
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single-arm, open-label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare-up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight-adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square-root transformation. Twelve-month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18-month interim analyses utilized BcPM with square-root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed-effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen-month interim analyses included 97 MOVE and 101 NHS individuals with post-baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene-treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid-associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene-treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Miositis Osificante , Osificación Heterotópica , Humanos , Miositis Osificante/tratamiento farmacológico , Teorema de Bayes , Osificación Heterotópica/tratamiento farmacológico , Pirazoles/uso terapéuticoRESUMEN
Today, it is anticipated most individuals diagnosed with single-ventricle malformation will survive surgical reconstruction through a successful Fontan operation. As greater numbers of patients survive, so has the recognition that individuals with Fontan circulation face a variety of challenges. The goal of a normal quality and duration of life will not be reached by all. The hurdles fall into a variety of domains. From a cardiovascular perspective, the Fontan circulation is fundamentally flawed by its inherent nature of creating a state of chronically elevated venous pressure and congestion, accompanied by a relatively low cardiac output. Ventricular dysfunction, atrioventricular valve regurgitation, and arrhythmia may directly impact cardiac performance and can progress with time. Problems are not limited to the cardiovascular system. Fontan circulatory physiology impacts a multitude of biological processes and health parameters outside the heart. The lymphatic circulation is under strain manifesting as variable degrees of protein-rich lymph loss and immune system dysregulation. Organ system dysfunction develops through altered perfusion profiles. Liver fibrosis is ubiquitous, and a process of systemic fibrogenesis in response to circulatory stressors may affect other organs as well. Somatic growth and development can be delayed. Behavioral and mental health problems are common, presenting as clinically important levels of anxiety and depression. Most striking is the high variability in prevalence and magnitude of these complications within the population, indicating the likelihood of additional factors enhancing or mitigating their emergence. We propose that optimal care for the individual with single ventricle and a Fontan circulation is ideally offered in a comprehensive multidisciplinary manner, with attention to elements that are beyond cardiac management alone. In this report, we share the concepts, our experiences, and perspectives on development of a clinic model-the "Fontan rehabilitation, wellness and resilience development" or FORWARD program. We provide insights into the mechanics of our multidisciplinary model of care and the benefits offered serving our growing population of individuals with a Fontan circulation and their families.
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Procedimiento de Fontan , Cardiopatías Congénitas , Disfunción Ventricular , Adolescente , Gasto Cardíaco Bajo , Niño , Procedimiento de Fontan/efectos adversos , Cardiopatías Congénitas/complicaciones , Ventrículos Cardíacos , Humanos , Disfunción Ventricular/complicacionesRESUMEN
The compassionate use of available medications with unproven efficacy is often in conflict with their clinical evaluation in placebo-controlled clinical trials. For ultra-rare diseases where no approved treatments exist, such as fibrodysplasia ossificans progressiva (FOP), routine clinical trial enrollment for available medications may be difficult to achieve. Therefore adaptive methods of evaluation are often desirable. Off-on-off-on (O4) approaches offer an opportunity to rapidly assess the potential symptomatic efficacy and tolerability of a medication with a limited number of patients and may aid in the design of more focused clinical trials that are amenable to enrollment. Here we report three children with classic FOP who had recalcitrant flare-ups of the back and who had been treated with an O4 regimen of imatinib. In all three children, fewer flare-ups, decreased swelling and improved function with activities of daily living were reported by the parents and treating physician when the children were "on" imatinib than when they were "off" imatinib. The median time to improvement on imatinib was 2-3 weeks. The anecdotal O4 experience with imatinib reported here in three children with FOP who had recalcitrant flare-ups of the back supports the design of a brief placebo controlled trial to assess the potential efficacy of imatinib in reducing the symptoms in children with refractory flare-ups of FOP. A tool to prospectively measure and quantitate flare-up symptoms is presently being developed and validated and will be used for such a study.
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Miositis Osificante , Osificación Heterotópica , Receptores de Activinas Tipo I , Actividades Cotidianas , Niño , Humanos , Mesilato de Imatinib/uso terapéutico , Miositis Osificante/tratamiento farmacológicoRESUMEN
OBJECTIVE: To evaluate growth in a population of patients with Fontan circulation. STUDY DESIGN: We performed a cross-sectional evaluation of patients followed in our multidisciplinary Fontan clinic from January 2011 through August 2015. We reviewed the historical data, anthropometry, clinical, and laboratory studies and performed bivariate and multivariate analysis of factors associated with height z score. RESULTS: Patients (n = 210) were included in the study at median age 11.07 years (8.3, 14.73 years) (43% female); 138 (65%) had a dominant right systemic ventricle and 92 (44%) hypoplastic left heart syndrome. Median age at completion of Fontan circulation was 31 months (7.6, 135.8 months). Median height z score was -0.58 (-1.75, 0.26). Twenty-five (12%) had current or past history of protein-losing enteropathy (PLE). Median height z score for those with current or past history of PLE was -2.1 (-2.46, 1.24). Multivariate analysis revealed positive associations between height z score and body mass index z score, time since Fontan, mid-parental height, dominant systemic ventricle type, and serum alkaline phosphatase. Height correlated negatively with known genetic syndrome, PLE, use of stimulant or oral steroid medication. CONCLUSIONS: Children with Fontan circulation have mild deficits in height, with greater deficits in those with PLE. Height z score improves with time postsurgery. Improving weight, leading to improved body mass index, may be a modifiable factor that improves growth in those who are underweight. Biochemical markers may be helpful screening tests for high-risk groups in whom to intensify interventions.
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Procedimiento de Fontan/efectos adversos , Crecimiento y Desarrollo , Enteropatías Perdedoras de Proteínas/etiología , Adolescente , Estatura , Peso Corporal , Niño , Estudios Transversales , Femenino , Ventrículos Cardíacos/anomalías , Ventrículos Cardíacos/cirugía , Humanos , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: Primary hyperparathyroidism (PHPT) in children and adolescents is uncommon. Data-driven guidelines for management in pediatric patients are limited. METHODS: We performed a retrospective cohort analysis of all patients (1997-2017) with PHPT ≤ 21 years of age who underwent parathyroidectomy at three institutions. Clinical and demographic variables were analyzed. Primary operative outcome was cure (normocalcemia > 6 months after surgery); secondary outcome was operative success (intraoperative parathyroid hormone decrease of ≥ 50%). RESULTS: We identified 86 patients with a median age of 17 years (IQR: 14, 19); 64% (n = 55) were female. The mean preoperative serum calcium was 11.7 mg/dL, median parathyroid hormone (PTH) was 110 pg/mL, and median urine calcium was 4.1 mg/kg/24 h. Preoperatively, sestamibi scan localized in 41/71 patients (58%); neck ultrasound localized in 19/44 (43%). The most common pathology at surgery was a single ectopic parathyroid adenoma in 71% (n = 61). A high incidence of ectopic adenomas (25%, n = 22) was observed, most commonly intrathymic (n = 13), followed by tracheoesophageal groove (n = 5), carotid sheath (n = 2), and intrathyroidal (n = 2). Of 56 patients with retrievable data > 6 months postoperatively, cure was achieved in 55 of 56 patients (98%). One patient who presented to us with parathyromatosis require subsequent reoperation. CONCLUSION: In this multi-institutional series of PHPT in children and adolescents, the majority were sporadic PHPT and were due to a single adenoma. We observed a high incidence of ectopic parathyroid adenomas, most commonly intrathymic. Given the high risk for ectopic adenoma in pediatric patients, parathyroid surgery in children and adolescents should be performed by experienced surgeons.
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Adenoma/complicaciones , Coristoma/complicaciones , Hiperparatiroidismo Primario/etiología , Enfermedades Linfáticas/complicaciones , Glándulas Paratiroides , Neoplasias de las Paratiroides/complicaciones , Timo , Adenoma/cirugía , Adolescente , Calcio/sangre , Calcio/orina , Coristoma/cirugía , Femenino , Humanos , Hiperparatiroidismo Primario/sangre , Hiperparatiroidismo Primario/cirugía , Enfermedades Linfáticas/cirugía , Masculino , Hormona Paratiroidea/sangre , Neoplasias de las Paratiroides/cirugía , Paratiroidectomía , Estudios RetrospectivosRESUMEN
BACKGROUND: Guidelines for treatment of primary hyperparathyroidism (PHPT) in young patients recommend surgery. Outcomes of minimally invasive parathyroidectomy (MIP) are well established in adults, but not in pediatric patients. OBJECTIVE: The objective of the study is to determine effectiveness of preoperative imaging and MIP aided by intraoperative PTH (ioPTH) measurement in children with primary hyperparathyroidism (PHPT). METHODS AND DESIGN: This is a retrospective chart review of diagnostic and follow-up data up to 12months post-MIP of patients with PHPT who underwent parathyroidectomy at the Children's Hospital of Philadelphia between January 1, 2009 and March 31, 2015. RESULTS: Data were available for 16 of 17 patients age 8-17years (11 females, 6 males): 2 had ectopic intrathymic adenomas while 14 had eutopic adenomas. Fifteen patients had ioPTH, including 14 who underwent MIP, defined as a 2cm central neck incision. All patients with data at 6months postparathyroidectomy (13/16) showed normal PTH and calcium. Ultrasound and sestamibi scans had a combined sensitivity of 87.5%. CONCLUSIONS: MIP is an appropriate alternative to standard neck exploration in pediatric patients with PHPT with a single parathyroid adenoma. ioPTH is especially useful to confirm cure and limit surgical exploration when imaging studies are negative. Sestamibi scans and ultrasound are complementary studies.
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Adenoma/cirugía , Hiperparatiroidismo Primario/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Neoplasias de las Paratiroides/cirugía , Paratiroidectomía/métodos , Adenoma/complicaciones , Adenoma/diagnóstico , Adolescente , Niño , Femenino , Humanos , Hiperparatiroidismo Primario/diagnóstico , Hiperparatiroidismo Primario/etiología , Masculino , Neoplasias de las Paratiroides/complicaciones , Neoplasias de las Paratiroides/diagnóstico , Estudios Retrospectivos , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento , UltrasonografíaRESUMEN
OBJECTIVE: To investigate the effect of teriparatide (parathyroid hormone [1-34]) on the healing of long bone nonunion fractures. METHODS: We performed a retrospective chart review of patients with fracture nonunion, aged 10 to 99 years who were treated with teriparatide at the Children's Hospital of Philadelphia or the Hospital of the University of Pennsylvania between November 2002 and January 2013. The primary endpoints were radiographic evidence of callus formation and fracture union, ability to bear weight without affected limb limp, and normal range of motion and strength. RESULTS: Six patients aged 19 to 64 years with tibial or femoral fractures that had not healed for 3 to 36 months were treated with teriparatide 20 µg/day. Accelerated healing of fracture nonunion was confirmed in 5 of 6 patients with time to complete union of 3 to 9 months. The shortest time to recovery was observed in younger patients without comorbidities. Treatment was well tolerated. CONCLUSION: Teriparatide is a promising treatment for nonunion fractures, but its response depends on associated comorbidities. The potential benefit of teriparatide as an adjunct to treat nonunion justifies randomized placebo-controlled trials to determine its efficacy and safety in broader populations.
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Fracturas del Fémur/tratamiento farmacológico , Fracturas no Consolidadas/tratamiento farmacológico , Teriparatido/uso terapéutico , Fracturas de la Tibia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Curación de Fractura/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Protein-losing enteropathy (PLE) is a rare but potentially devastating complication of single-ventricle physiology after the Fontan operation. Although abnormal bone mineral density (BMD) is a known complication of chronic disease and congenital heart disease, no reports have described BMD in patients with PLE. This study investigated a cross-sectional sample of children and young adults with a confirmed diagnosis of PLE. Serum levels of 25(OH)D, calcium, total protein, and albumin were recorded from the first outpatient encounter with each subject. Corrected calcium (cCa) was calculated from the serum calcium and albumin levels. Dual-energy X-ray absorptiometry (DXA) was used to measure BMD, and z-scores were generated using appropriate software. DXA results were available for 12 patients (eight males and four females). The age at DXA ranged from 7.2 to 25.2 years. The mean z-score was -1.73 standard deviation (SD) for the entire cohort, with 42 % z-scores below -2 SDs. Serum 25(OH)D levels were abnormal in 58 % of the patients. There was a positive correlation between cCa and DXA z-score and a negative correlation between total protein and DXA z-score. Patients receiving corticosteroid therapy had a significantly lower DXA z-score than those not receiving corticosteroids (-3.15 vs. -0.31; p = 0.02). Children with PLE are at risk for abnormal BMD compared with age- and sex-matched control subjects. In the study cohort, corticosteroid exposure, a marker of disease severity, appeared to be associated with decreased BMD. Routine bone health screening is warranted for children with PLE, particularly those receiving corticosteroid therapy.
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Densidad Ósea , Procedimiento de Fontan , Cardiopatías Congénitas/cirugía , Enteropatías Perdedoras de Proteínas/etiología , Absorciometría de Fotón , Adolescente , Adulto , Albúminas/metabolismo , Biomarcadores/sangre , Proteínas Sanguíneas/metabolismo , Calcio/sangre , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Vitamina D/sangreRESUMEN
Bone formation and osteoblast differentiation require the functional expression of the Runx2/Cbfbeta heterodimeric transcription factor complex. Runx2 is also a suppressor of proliferation in osteoblasts by attenuating cell cycle progression in G(1). Runx2 levels are modulated during the cell cycle, which are maximal in G(1) and minimal beyond the G(1)/S phase transition (S, G(2), and M phases). It is not known whether Cbfbeta gene expression is cell cycle controlled in preosteoblasts nor how Runx2 or Cbfbeta are regulated during the cell cycle in bone cancer cells. We investigated Runx2 and Cbfbeta gene expression during cell cycle progression in MC3T3-E1 osteoblasts, as well as ROS17/2.8 and SaOS-2 osteosarcoma cells. Runx2 protein levels are reduced as expected in MC3T3-E1 cells arrested in late G(1) (by mimosine) or M phase (by nocodazole), but not in cell cycle arrested osteosarcoma cells. Cbfbeta protein levels are cell cycle independent in both osteoblasts and osteosarcoma cells. In synchronized MC3T3-E1 osteoblasts progressing from late G1 or mitosis, Runx2 levels but not Cbfbeta levels are cell cycle regulated. However, both factors are constitutively elevated throughout the cell cycle in osteosarcoma cells. Proteasome inhibition by MG132 stabilizes Runx2 protein levels in late G(1) and S in MC3T3-E1 cells, but not in ROS17/2.8 and SaOS-2 osteosarcoma cells. Thus, proteasomal degradation of Runx2 is deregulated in osteosarcoma cells. We propose that cell cycle control of Runx2 gene expression is impaired in osteosarcomas and that this deregulation may contribute to the pathogenesis of osteosarcoma.
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Ciclo Celular/fisiología , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Subunidad beta del Factor de Unión al Sitio Principal/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Osteosarcoma/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad beta del Factor de Unión al Sitio Principal/genética , Inhibidores de Cisteína Proteinasa , Fase G1/fisiología , Expresión Génica/genética , Humanos , Leupeptinas/farmacología , Ratones , Mitosis/fisiología , Osteoblastos/citología , Osteoblastos/metabolismo , Osteosarcoma/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma , Ratas , Ubiquitinación/efectos de los fármacosRESUMEN
CONTEXT: T(3) action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T(3) uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T(3) levels. OBJECTIVE: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T(3). DESIGN: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T(3) uptake, 2) T(3) metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry. RESULTS: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8. CONCLUSION: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T(3) levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T(3) in central neurons.
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Enfermedades Genéticas Ligadas al Cromosoma X/genética , Discapacidad Intelectual/genética , Transportadores de Ácidos Monocarboxílicos/genética , Trastornos Psicomotores/genética , Triyodotironina/sangre , Línea Celular Tumoral , Codón sin Sentido , Eliminación de Gen , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Humanos , Discapacidad Intelectual/metabolismo , Neuronas/metabolismo , Mutación Puntual , Trastornos Psicomotores/metabolismo , Sitios de Empalme de ARN , Simportadores , Transfección , Triyodotironina/farmacocinéticaRESUMEN
Longitudinal bone growth occurs by a process called endochondral ossification that includes chondrocyte proliferation, differentiation, and apoptosis. Recent studies have suggested a regulatory role for intracellular Ca(2+) (Ca(i) (2+)) in this process. Indirect studies, using Ca(2+) channel blockers and measurement of Ca(i) (2+), have provided evidence for the existence of Ca(2+) channels in growth plate chondrocytes. Furthermore, voltage-gated Ca(2+) channels (VGCC), and specifically L- and T-type VGCCs, have been recently described in murine embryonic growth plates. Our aim was to assess the effect of L-type Ca(2+) channel blockers on endochondral ossification in an organ culture. We used cultures of fetal rat metatarsal rudiments at 20 days post gestational age, with the addition of the L-type Ca(2+) channel blockers verapamil (10-100 microM) or diltiazem (10-200 microM) to the culture medium. Longitudinal bone growth, chondrocyte differentiation (number of hypertrophic chondrocytes), and cell proliferation (incorporation of tritiated thymidine) were measured. Verapamil dose-dependently decreased growth, the number of hypertrophic chondrocytes, and cell proliferation, at concentrations of 10-100 microM. Growth and the number of hypertrophic chondrocytes decreased significantly with diltiazem at 50-100 microM, and proliferation decreased significantly at concentrations of 10-200 microM. Additionally, there was no increase in apoptosis over physiological levels with either drug. We confirmed the presence of L-type VGCCs in rat rudiments using immunohistochemistry, and showed that the antagonists did not alter the pattern of VGCC expression. In conclusion, our data suggest that L-type Ca(2+) channel activity in growth plate chondrocytes is necessary for normal longitudinal growth, participating in chondrocyte proliferation and differentiation.
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Huesos , Canales de Calcio Tipo L/metabolismo , Condrocitos/metabolismo , Placa de Crecimiento/citología , Osteogénesis/fisiología , Animales , Apoptosis/fisiología , Huesos/citología , Huesos/metabolismo , Huesos/fisiología , Bloqueadores de los Canales de Calcio/farmacología , Condrocitos/citología , Condrocitos/efectos de los fármacos , Diltiazem/farmacología , Osteogénesis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Verapamilo/farmacologíaRESUMEN
Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gene of which is located on the X chromosome. We tested whether mutations in MCT8 cause severe psychomotor retardation and high serum triiodothyronine (T3) concentrations in five unrelated young boys. The coding sequence of MCT8 was analysed by PCR and direct sequencing of its six exons. In two patients, gene deletions of 2.4 kb and 24 kb were recorded and in three patients missense mutations Ala150Val, Arg171 stop, and Leu397Pro were identified. We suggest that this novel syndrome of X-linked psychomotor retardation is due to a defect in T3 entry into neurons through MCT8, resulting in impaired T3 action and metabolism.
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Enfermedades Genéticas Ligadas al Cromosoma X/genética , Discapacidad Intelectual/genética , Transportadores de Ácidos Monocarboxílicos/genética , Mutación , Trastornos Psicomotores/genética , Triyodotironina/metabolismo , Niño , Preescolar , Eliminación de Gen , Humanos , Lactante , Discapacidad Intelectual/sangre , Masculino , Transportadores de Ácidos Monocarboxílicos/metabolismo , Mutación Missense , Trastornos Psicomotores/sangre , Simportadores , Triyodotironina/sangreRESUMEN
BACKGROUND: Achondroplasia and hypochondroplasia are skeletal dysplasias of autosomal dominant inheritance that represent different degrees of severity of the same pathological entity. Both dysplasias are caused by mutations in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene. In achondroplasia more than 95% of the cases studied to date carry the same mutation (G380R). Hypochondroplasia represents a greater clinical and genetic heterogeneity, possibly being confused with "idiopathic short stature". The N540K mutation has been detected in 50-70% of cases of hypochondroplasia and mutations at the 650 locus in approximately 2.8%. AIM: To assess the frequency of N540K and G380R mutations, and changes at the 650 locus in Chilean patients with idiopathic disproportionate short stature, hypochondroplasia and achondroplasia. PATIENTS AND METHODS: We studied 21 patients referred for idiopathic short stature, 5 with clinically suspected hypochondroplasia and 4 with achondroplasia. The G1138A, G1138C (G380R), and C1620, C1620A (N540K) mutations and the nucleotide changes at the 650 locus were studied using PCR and restriction analysis of genomic DNA. RESULTS: Three out of five hypochondroplasia patients were heterozygous for the N540K mutation. All of the 4 patients with achondroplasia presented the G1138A mutation. None of these mutations were found in patients with idiopathic short stature. CONCLUSION: Chilean patients with hypochondroplasia and achondroplasia have the same mutations described in other ethnic groups. The identification of mutations in 3 out of 5 patients with hypochondroplasia shows that this analysis is a useful tool for its diagnostic confirmation. In short stature the molecular study should only be indicated in those cases presenting other clinical and/or radiological features of hypochondroplasia.